The ErbB family of receptor tyrosine kinases mediates the development and maintenance of a variety of tissue types, including cardiac and neural tissues, and receptor overexpression or aberrant activation can lead to the formation and progression of many solid tumors types. While the mechanisms by which RTKs regulate cellular growth properties have received much attention over the years, mechanisms modulating the efficiency of RTK signaling remain largely unexplored. The efficiency of ErbB response to ligand binding must be very tightly regulated to ensure sufficient signaling activity to mediate developmental processes, while preventing the hyper-signaling that could lead to cancer. The overall objective of this project is to understand the mechanisms by which receptor modulation pathways operate. Two unrelated ErbB modulator proteins, Nrdp1 and Muc4, influence the ability of the ErbB2/ErbB3 heterodimeric receptor complex to respond to the growth factor NRG1 by influencing receptor trafficking and localization. Nrdp1 is an E3 ubiquitin ligase that suppresses NRG1 signaling by mediating the ubiquitination and degradation of ErbB3. Specific Aim 1 of the proposed studies examines the molecular mechanisms by which Nrdp1 is regulated, focusing on the activities and phosphorylation of two deubiquitinating enzymes that act in the Nrdp1 pathway. Muc4 is a membrane mucin that physically interacts with ErbB receptors and potentiates the response of the ErbB2/ErbB3 complex to NRG1. This protein inhibits receptor internalization, resulting in the net translocation of receptors from intracellular compartments to the surface of tumor cells. Specific Aim 2 examines the molecular mechanisms by which Muc4 alters receptor trafficking and localization.